Auditory deficits are present in a growing population of millions of elderly listeners. A fundamental gap in knowledge is that central auditory representations of the sounds most affected by aging are poorly understood due to limited in vivo measurements and due to a disconnect between the in vivo responses and their cellular neural bases. The long-term goal of this research is to discover how alterations of cellular physiology in the central auditory pathway of aged animals give rise to altered neural representations at the single-neuron, local network and population levels, in order to target hearing maintenance or recovery programs based on mechanistic hypotheses. Given this goal, the objective of this proposal is to link non-invasive envelope-following and frequency-following responses to inferior colliculus (IC) spiking responses and local field potentials (LFPs) in vivo and to biophysical models of IC neurons. Our central hypothesis is that many age-related auditory deficits can be explained by a small number of critical changes in cellular neurophysiology, such as reduced inhibition, whose consequences can be observed in vivo by measuring the activities of small populations of IC neurons or large populations of brainstem and IC neurons in response to appropriate non-speech and speech-like sounds. The rationale for this research is that there have been few attempts to link diagnostic in vivo data to the underlying neural circuitry that generate aberrant responses, which hampers progress towards remedying the deficits. The proposal objective will be addressed by the following aims: Aim 1) Identify the sounds and shared acoustic features that generate aberrant envelope and frequency following responses in aged animals to bridge animal and human auditory assessments. Aim 2) Determine changes in the spiking activities and LFPs of IC neurons during aging and their correspondence to changes in the envelope following responses evoked by the same sounds. Aim 3) Reproduce in vivo IC responses and predict responses to sounds in young and aged animals using detailed biophysical IC models to distinguish between different cellular mechanisms in aging. The expected contribution of the proposed research is to create a clinic to channels knowledge loop wherein non-invasive diagnostic measurements of central auditory activity in animals are linked to in vivo single neuron responses, LFPs and detailed mechanistic models of IC neurons. This contribution is significant because connecting in vivo electrophysiological measurements with their cellular bases creates a powerful framework in which to iteratively identify factors that contribute to age-related central auditory decline and predict rapidly the consequences of potential treatments that affect those factors. The proposed research is innovative because in vivo electrophysiological measurements of clinically and behaviorally relevant sounds taken at the population, local network, and single/multiunit levels are informed and constrained by detailed cellular and synaptic models of the central auditory system, rather than by abstract or anatomically based models. This will provide targets for pharmacologic or behavioral therapy at each level. PUBLIC HEALTH RELEVANCE: The proposed project is relevant to public health because it progresses towards establishing a clear link between non-invasive human and animal auditory neurophysiologic diagnostics and the cellular mechanisms that generate those responses in young and old listeners. Impacts relevant to the NIH's mission will emerge in the form of diagnostic stimuli with the ability to pinpoint specific types of temporal and spectral processing deficits in aging, along with the ability to identify and predict the effects of numerous potential therapeutic targets in vivo based on their cellular modes of action.